The invention relates to adhesives for medical applications and means for haemostasis. In particular, the invention relates to a kit for the manufacture of an adhesive suitable for adhering hard and soft tissue to each other, for the closure of wounds, as well as the adhesive itself and its uses in the medical field. The kit and the corresponding adhesive comprise, as individual components, substrates of the polyphenoloxidase as well as polyphenoloxidases as such. Furthermore, the invention relates to novel haemostatics as well as the combined use of haemostatics and adhesives in the closure of wounds.
The development of novel adhesives for tissue that can be applied, especially in problematic cases, has strongly gained importance in the past few years. Adhesives for tissue on the basis of acrylate used so far can only be applied to superficial wounds, since acrylates are not decomposed biologically and could impose a toxic hazard. One focus is, therefore, on the biological decomposability of the used materials. Therefore, polymers of vegetable or animal origin are of special importance in the manufacture of adhesives. Mussels can have strong bonds with various carrier substrates under water. The reason for this is the formation/excretion of MAPs (mussel adhesive proteins). MAPs consist of a number of proteins that can vary depending on the type of mussel. In U.S. Pat. No. 5,015,677 A, a mussel adhesive is protected containing as an essential component a very special decapeptide isolated from mussels. This decapeptide contains dehydroxyaromates as substituents of very special amino acids that form an essential component of the peptide chain. The peptide chains are then bonded with each other by means of a tyrosinase. Further satisfying solutions that make it possible to bond bones with implants by means of an adhesive are not known.
EP 0 947 142 discloses increasing the molecular weight of proteins by crosslinking by means of multi-copper enzymes. The described increasing of the molecular weight of the substrate proteins occurred seventeen hours after incubation. The proteins crosslinked using the method of EP 0 947 142 are especially suitable for the use in food, for example for modifying the consistence of sausage. Crosslinking of proteins by means of substituted dihydroxyaromates is not disclosed in EP 0 947 142.
If adhesives for wounds are intended to be used in case of strongly bleeding wounds, there is the danger that adhesive components are washed away with the bloodstream and the adhesion occurs at a site where it is not desired. Thus, the danger of thrombosis is strongly increased. Acute treatment of strongly bleeding wounds is still a problem that is not solved satisfyingly. Haemostasis according to the state of the art can be achieved by
(a) Denaturation of proteins, for example by means of metal salts
(b) Microporous biopolymers or biopolymers having a great inner surface, respectively. They resorb water, and, therefore, cause concentration of blood cells as well as coagulation factors. Polysaccharides consisting of poly-N-acetyl-glucosamines or chitosan have proved to be especially advantageous. They are, for example, contained in the skeleton of insects, but also in algae. Biopolymers such as gelatin, collagen, fibrin sponges or oxidized cellulose have a great inner surface. A concentration of coagulation factors is caused by absorption onto these great surfaces.
(c) Enzymes, especially by thrombin or proteolytic enzymes having thrombin-like activity with or without the addition of calcium.
(d) Highly concentrated coagulation factors
(e) Combinations of (c) and (d)
(f) Calcium alginates
(g) Alumosilicate synthesis products having a microporous structure.
Alumosilicate synthesis products used for haemostasis are alkaline or alkaline-earth alumosilicates of differing composition.
The company Z-Medica, U.S. has developed a synthesis product on the basis of synthesized earth-alkali alumosilicates that completely dehydrate at above 400° C. for the immediate treatment of war injuries and for emergency use. Because of the strongly exothermic reaction, blood is dehydrated causing haemostasis. The synthesis product is directly applied to the wound as a granulate. It is marketed under the designation “Quikclot.” A disadvantage has been described for this product in that because of the exothermic reaction (temperatures up to 60° C.) adjacent tissue can be damaged (Journal of Trauma 54 (2003) 6, 1077-1082).
Synthetic lithium alumosilicates (EP 1 176 991 A1, WO 00/69480) were developed especially for the treatment of wounds and are marketed under the designation CERDAC. In the case of CERDAC, a microporous ceramic product is produced using high temperatures (>1000° C.) in order to obtain optimal treatment of wounds.
The capillary force action is too low, apart from the partly complicated production, to satisfy all requirements.
A great problem is still the possible chronification of wounds, especially in case of risk patients. This so far cannot be avoided for certain, and the treatment of such wounds is still very difficult. Chronification often involves an infection of the wound.
Four million patients suffer from chronically open wounds in Germany alone. The annual costs amount to E1.7 to £3.2 billion. The treatment of chronic wounds so far has not been solved satisfyingly.